Method development (design selection).
Fundamental to design selection is the method-development phase. To develop a QbD method, the method performance criteria
must be understood as well as the desired operational intent that the eventual end user would wish to see in the method. To
deliver the latter, methods must take into account the VoC.
The method development process should use an agreed standardized approach between development and manufacturing. For example,
within GSK there is a companywide strategy for chromatographic methods that is based on the best scientific knowledge and
expertise that is aimed at minimizing unnecessary and detrimental diversity. The design of the method is a key decision. Issues
that may easily be solved by appropriate selection at this point are likely to be more difficult to fix later, if trying to
optimize a poor method not suited to meet its method-performance criteria. Consideration also must be given to whether on-line
methods can be used in place of traditional lab-based methods. This assessment takes place once the CQAs for the process have
been identified.
Through a thorough understanding of the design intent, methods for commercial operation would be designed only for those specific
impurities relevant to the commercial product. Historically, the methods transferred into quality control laboratories have
often taken into account potential impurities detected in earlier routes of synthesis, which cannot be formed from the commercial
route or monitor theoretical degradation products that, in practice, are not formed during routine stability studies. Significant
opportunities exist to identify what is truly critical to control and reduce method complexity once sufficient process understanding
is obtained.
Risk assessment and analytical design-space definition (control definition).
It is imperative to reach a high degree of confidence that the analytical method will meet all method performance criteria
under all conditions of use as it progresses through the lifecycle. This confidence level can be achieved by using a rigorous
approach for identifying all the potential method factors that may need to be controlled to ensure method performance and
through the use of risk assessment tools and prioritized experimentation that eliminate areas of risk.
To maximize the benefits of performing a risk assessment, the analysts who have developed the method should work as a team
with the analysts who will be using the method in manufacturing. To fully understand the method, a walk-through is recommended
that involves all the analysts observing one analyst using the method from start to finish in the manufacturing environment.
Each of the steps within the method can then be mapped out separately (e.g., sample preparation, dissolution, extraction,
chromatographic separation, data analysis).
Figure 2: Fishbone diagram created for an HPLC assay and impurities method.
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A cause-and-effect diagram, also known as a fishbone or Ishikawa diagram, can then be used after the walk through to facilitate
brainstorming of all the potential factors that may influence the method performance criteria (15). Mind-mapping software
can be valuable in this exercise because it facilitates the collection of all the detailed factors that represent potential
variables in the method. Figure 2 shows an example of part of a fishbone performed on a tablet HPLC assay–impurities method.
Under each subheading, there are further factors (not shown in Figure 2). For example, for HPLC, subfactors include the pump,
dwell volume, autosampler, and detector. With information obtained from operating the method and the walk-through, analysts
are encouraged to draw upon their past experience of the operation of similar methods on various products to ensure that previous
lesssons learned are incorporated into the risk assessment. Establishing a corporate knowledge repository for important factors
for each technique can facilitate this learning process.
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